CN116115598A - Application of isoflavone alcohol compound in preparation of medicament for preventing or treating metabolic syndrome - Google Patents
Application of isoflavone alcohol compound in preparation of medicament for preventing or treating metabolic syndrome Download PDFInfo
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- CN116115598A CN116115598A CN202111349440.4A CN202111349440A CN116115598A CN 116115598 A CN116115598 A CN 116115598A CN 202111349440 A CN202111349440 A CN 202111349440A CN 116115598 A CN116115598 A CN 116115598A
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Abstract
The invention relates to the field of biomedical science, discloses application of an isoflavone alcohol compound in preparing a medicament for preventing or treating metabolic syndrome, and particularly discloses application of an isoflavone alcohol tail in preparing a medicament with a ceripoprotein receptor agonist activity, and application in preparing a medicament for preventing or treating pathophysiological or psychological diseases characterized by low expression or activity reduction of ceripoprotein II or ceripoprotein-like peptides, and application in preparing a medicament for treating and/or preventing metabolic syndrome. The compound can specifically activate the tail vasopressin receptor, and has the effects of obviously promoting the reduction of the triglyceride content of liver cells, reducing the fat accumulation of the liver cells and regulating the metabolism of glycolipid. The compound has novel effect, easy synthesis, low dosage and good application and development prospect.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to application of a novel compound with urotenin-2 receptor (UT) agonist activity in preventing or treating pathophysiological diseases characterized by low expression or activity reduction of urotenin II or urotenin-like peptide. In particular to the application in preparing the medicine for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications.
Background
Tail vasopressin II (U-II) is a polypeptide which was first isolated from the neurosecretory system of goby (Gillichthys mirabilis) and then cloned in humans. U-II is a highly active endogenous uropressin receptor (UT receptor) peptide agonist. The UT receptor is a G protein-coupled receptor that can be transduced by gαq signaling. Peptides such as U-II have a cyclic structure and contain polypeptides having a length of 11 to 15 amino acids. Human U-II (hU-II) is a polypeptide of 11 amino acids. UT receptors, also known as GPR14, are involved in the regulation of vasoconstriction. In mammals, mRNA of U-II precursor (UTS 2) and UT receptor gene (UTS 2R) is widely expressed in the central nervous system and surrounding tissues including brain, kidney, liver, lung, pancreas, skeletal muscle and other tissues, blood vessels and heart cells. Consistent with the broad distribution of U-II and UT receptors, the uropressurized system is associated with a number of pathological conditions including atherosclerosis, heart failure, hypertension, renal disease, and diabetes.
With the deep research of the mechanism of the U-II system, the research and development of the drug taking the drug as a target spot are important points of the research, and the drug enters clinical experiments. At present, agonists and antagonists of UTR are found, which are more studied as antagonists and can be classified into polypeptides and non-peptides according to the substance characteristics. Among them palosuran is the most deeply studied and widely studied UTR inhibitor, which entered clinical trials in 2003 with diabetic nephropathy as an indication, but eventually ended up in phase ii clinical trials in 2007 due to pharmacodynamics imperfections. The palosuran has been reported to improve kidney disease, cardiovascular disease, lung injury, etc. in diabetic patients. Another study shows that U-II is associated with reduced insulin secretion and impaired insulin signaling pathway, but palosuran does not exhibit the effect of reversing this phenomenon, and specific mechanisms and reasons need to be further explored. Generally, the drug research taking UTR as a target point is mostly in a stagnation state at present, and most of reasons for unobvious curative effect are not obvious. We have found that U-II itself improves glycolipid metabolism and, on the other hand, explains the reasons for the poor effect of its antagonists, and also that the vasopressin receptor agonists play an important role in fat regulation and glucose tolerance regulation. Widening the selection field of anti-obesity and type 2 diabetes is therefore important to develop novel drugs with uropressin receptor agonism.
Metabolic syndrome is a complex group of metabolic disorder syndrome, is a pathological state of abnormal aggregation of various metabolic components, and is a risk factor for causing diabetic cardiovascular and cerebrovascular diseases. It has the following characteristics: (1) a variety of metabolic disorders, including obesity, hyperglycemia, hypertension, dyslipidemia, which are the pathological basis for heart and brain vascular disease and diabetes; (2) there is a common pathological basis, and the common cause of the compounds is insulin resistance and hyperinsulinemia caused by obesity, especially central obesity; (3) can cause accumulation of various diseases, such as hypertension, coronary heart disease, cerebral apoplexy, and even some cancers.
Obesity is a chronic metabolic disease caused by excessive accumulation of excessive energy in the body in adipose tissue, and is a significant risk factor affecting cardiovascular and cerebrovascular diseases, diabetes, tumors, and the like. Limiting energy intake such as diet and taking weight-reducing drugs; or increasing energy expenditure such as exercise, which can lead the weight of the obese patients to rebound due to poor compliance or side effects of the drugs, thereby being prohibitive for weight loss. Therefore, how to prevent and treat obesity, which is a global health problem, is finding a safe and effective treatment method to be a hot spot problem for research by medical and nutritionist at home and abroad.
Currently, drugs for treating obesity clinically mainly include appetite suppressants: a medicine for central appetite suppression and gastrointestinal hormone for regulating appetite. Acting on peripheral fat synthesis and decomposition: acts in the gastrointestinal tract to reduce fat absorption (lipase inhibitors and sodium-glucose co-transporter 2 inhibitors). Acts on adipose tissue to reduce fat synthesis and promote release and decomposition. The medicine for treating type 2 diabetes mainly comprises: insulin and analogues thereof, sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinedione derivatives, insulin secretagogues, chinese patent medicines and the like. There is currently no weight loss product that reduces metabolic syndrome and complications.
The invention is thatThe molecular formula of the (4H-1-benzopyran-4-one-8- (1, 1-dimethyl-2-proline-1-alkene) -3,5, 7-trihydroxy-2-6- (8-hydroxy-2, 2-dimethyl-2H-1-benzopyran)) compound 11799 is C 25 H 24 O 7 The molecular weight was 436.45 and the predicted boiling point at 760 torr was 650.7 ℃. Compound 11799 is a flavonol compound isolated from ethanol extract of leaves of Sonchus arvensis of Moraceae. Branches and leaves of chicory are often used as diuretics, supplements and edema inhibitors in Chinese folk medicine, but are not currently being investigated for the pharmacological activity of compound 11799.
The compound 11799 is a new discovery obtained through experimental study. The new invention relates generally to the preparation of medicaments and pharmaceutical combinations. The application of the composition in the preparation of medicaments for preventing or treating pathophysiological diseases characterized by low expression or activity of the ceripoprotein II or ceripoprotein-like peptide and the receptor thereof, in particular the application in the preparation of medicaments for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications is provided for clinic. The use of the related compound 11799 in the pathophysiological diseases characterized by low expression or activity reduction of the ceripoprotein II or ceripoprotein-like peptide and the receptor thereof, in particular in the preparation of medicaments for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications, has not been reported directly or indirectly.
Disclosure of Invention
The invention aims to solve the technical problem of providing an application of a compound with the activity of a cermetin receptor agonist in preparing a medicament for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
(1) The present invention provides the use of a compound of formula (I) (i.e., compound 11799) in the manufacture of a medicament having a vasopressin receptor agonist activity.
(2) The invention provides application of a compound shown as a formula (I) in preparing a medicament for preventing or treating pathophysiological or psychological diseases characterized by low expression or activity reduction of ceropressin II or ceropressin-like peptide.
(3) The invention provides application of a compound shown as a formula (I) in preparing a medicament for treating and/or preventing metabolic syndrome. Wherein the metabolic syndrome comprises obesity, diabetes, diabetic complications, fatty liver, dyslipidemia and hypertension. The metabolic syndrome comprises pathological states of metabolic disturbance of protein, fat and carbohydrate of human body caused by various reasons.
The diabetes mellitus comprises type 1 diabetes mellitus and type 2 diabetes mellitus; the obesity comprises obesity caused by congenital, acquired and pharmaceutical reasons; the diabetic complications refer to large and small vascular lesions of diabetes; the fatty liver comprises liver steatosis caused by various reasons; the dyslipidemia comprises hypertriglyceridemia, low-high density lipoproteinemia and hypercholesterolemia; the hypertension includes an increase in systolic and/or diastolic blood pressure, with or without functional or organic impairment of the heart, brain, kidney organs.
Further, the diabetic complications include diabetic nephropathy, diabetic peripheral circulation dysfunction, diabetic peripheral neuropathy, diabetic eye disease, diabetic myopathy, diabetes complicated with hyperlipidemia.
(4) The invention provides an application of a pharmaceutical composition in preparing medicines with the activity of a ceropressin receptor agonist, in preparing medicines for preventing or treating pathophysiological or psychological diseases characterized by low expression or activity reduction of ceropressin II or ceropressin-like peptides, and in preparing medicines for treating and/or preventing metabolic syndrome, which is characterized in that the pharmaceutical composition contains an effective dose of a compound shown as a formula (I) and a medicinal excipient; the pharmaceutical compositions include controlled release, sustained release formulations and forms of microsomal drug delivery systems.
The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions thereof in an amount of from 0.1 to 95% by weight.
The dosage of the pharmaceutical composition of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, suitable dosages of the compounds of the present invention are in the range of 0.001 to 150mg/kg body weight, preferably 0.1 to 100mg/kg body weight, more preferably 1 to 60mg/kg body weight, and most preferably 2 to 30mg/kg body weight per day. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means. The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, cutaneous, vaginal, rectal, etc. The dosage form may be a liquid, solid or semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like. The compound of the invention can be prepared into common preparations, slow release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the compounds of the present invention into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets. In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used to prepare the tablets of the compounds of the invention may also be used to prepare capsules of the compounds of the invention. For the preparation of the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture may be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator may be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol, glucose, etc. can be added as propping agent for preparing lyophilized powder for injection. In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired. For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
Beneficial technical effects
1. The compounds (I) of the present invention modulate the activity of the tail vasopressin receptor. The use of the compounds of the invention for modulating the activity of the vasopressin receptor is first disclosed.
2. The compound (I) of the present invention can be used for preventing or treating a pathophysiological disease characterized by low expression or reduced activity of ceropressin II or a ceropressin-like peptide and its receptor. Reports on this use of the present compounds are disclosed for the first time.
3. The compound (I) can be used for preparing medicines for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications. The application of the compound in the aspect is disclosed for the first time, and the selection drugs of related diseases are widened.
4. Internationally, patents on cardiovascular regulation are presently disclosed for uropressin agonism (U.S. patent No. 4533654, date 1985, 8, 6). Our earlier studies reported for the first time the effect of ceriposide agonism in improving metabolic syndrome, obesity and type 2 diabetes (use of a polypeptide in the preparation of a medicament for preventing or treating metabolic syndrome, application number CN110038114 a). The influence of the compound (I) on the aspect of the tail vasopressin system in the invention is not disclosed in the related papers and patents at home and abroad.
3. The compounds of the invention are useful for the prevention or treatment of pathophysiological conditions characterized by low expression or reduced activity of ceripoxin II or ceripoxin-like peptides and their receptors, via novel targets. The application of the Chinese medicinal composition in preparing medicaments for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications. The invention is characterized in that the tail vasopressin system is targeted and the therapeutic and preventive effects are achieved. The medicine is safe and reliable. The medicine has obvious advantages when being developed as a medicine.
Drawings
FIG. 1. Results of docking of compound 11799 of the present invention to a model of the vasopressin receptor protein.
Figure 2 ADMET prediction of compound 11799 of the present invention.
FIG. 3 shows that compound 11799 of the present invention dose-dependently activates the ceripoprotein receptor at a half-maximal effective concentration of 8.97 x 10 -8 M。
FIG. 4A compound 11799 of the present invention is specific for the activation of the vasopressin receptor and does not activate other GPCR receptors.
FIG. 5. Effect of the compound 11799 of the present invention on glucose uptake by HepG2 liver cells.
FIG. 6 effect of the compound 11799 of the present invention on lactate release from HepG2 liver cells.
FIG. 7 effect of the compound 11799 of the present invention on HepG2 liver cell viability.
Detailed Description
The use of compound (I), also referred to as 11799 in this example, in modulating the activity of the vasopressin receptor, to prevent or treat pathophysiological conditions characterized by low expression or reduced activity of vasopressin II or vasopressin-like peptides and their receptors, is further described below in connection with the invention. The application of the Chinese medicinal composition in preparing medicaments for treating and/or preventing metabolic syndrome/type 2 diabetes/obesity/diabetes/fatty liver complications.
The following examples illustrate the invention in more detail, without any limitation thereof. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible in light of the above teachings and are intended to be within the scope of the invention.
EXAMPLE 1 dissolution and use of Compound 11799
Example 2 docking of Compound 11799 with a model of the vasopressin receptor protein
The experimental method comprises the following steps: the pdb file of the tail vasopressin receptor protein structure and the sdf file of compound 11799 were introduced into the Discovery Studio, and protein-ligand docking was performed using the cdOCKER flexible docking method in the Discovery Studio. Firstly, treating a compound and a Protein by using 'preparation links' and 'preparation Protein', defining the Protein as a receptor molecule, and predicting an active site of a receptor structure; the CDOCKER module in Receptor-Ligand Interactions was used to interface the protein with compound 11799 and set the corresponding parameters. And outputting a docking result after the program is operated, and analyzing the docking result.
Experimental results: molecular docking is a theoretical simulation method that studies intermolecular interactions (such as ligands and receptors) and predicts binding patterns and affinities thereof, and it is generally believed that the lower the energy is when the conformation of ligand binding to receptor is stabilized, the greater the probability of action. The binding energy of compound 11799 to the receptor protein was-12.32 kcal/mol, suggesting that the binding activity of compound 11799 to the receptor is higher. The two-dimensional plan view of the ligand-protein interaction generated by the compound 11799 and the receptor is shown in figure 1, the compound 11799 forms hydrogen bond with the amino acid residue Arg81 and forms Pi-Pi with the amino acid residue PYR87, and the effect of molecules and proteins is increased. The results are shown in FIG. 1.
EXAMPLE 3 evaluation of the patentability of Compound 11799
The experimental method comprises the following steps: the ADMET module in Discovery Studio software is used for importing the sdf file of the compound 11799 into DS software, selecting Calculate Molecular Properties from the Small molecular module to click ADMET descriptors for parameter setting, clicking operation, and predicting the absorption, distribution, metabolism, excretion and toxicity of the compound to obtain data of the compound 11799 in aspects of passive intestinal absorption, water solubility at 25 ℃, blood brain barrier penetrability, human cytochrome CYP4502D6 enzyme binding, hepatotoxicity, plasma protein binding and the like.
Experimental results: ADMET prediction results are shown in fig. 2. Compound 11799 has water solubility value log SW of-5.17, and CYP4502D6 enzyme inhibition number of 2.14e-07, and no inhibition in 0 level range. Compound 11799 had a hepatotoxicity measurement of 0.022 and was free of hepatotoxicity. Compound 11799 has a binding value of 4.13 to plasma proteins, suggesting that we may have a major portion of the drug in the plasma still free and only a minor portion bound to plasma proteins. The results are shown in Table 1 and FIG. 2.
ADMET prediction of compound 11799 of table 1
EXAMPLE 4 activation of the vasopressin receptor by Compounds 11799
The experimental method comprises the following steps: HEK293 cells were cultured in a high sugar culture medium of 4.5g/L DMEM containing 10% inactivated fetal bovine serum at 37℃in 5% CO 2 In a cell incubator. When the cell density reached 80%, subculture was performed at a ratio of 1:3. When the cell fusion reached 70%, the original medium was discarded and the culture was continued with 8ml DMEM for 4 hours. After 4h, 4ml of DMEM was aspirated from the medium and 4ml of DMEM medium containing 10% foetal calf serum was supplemented. The transfection solution was prepared in a ratio of DMEM: UTR per dish, PEI=800. Mu.l: 10. Mu.g: 40. Mu.l, and the amount of transfection reagent was adjusted according to the plasmid concentration. Mixing the transfection solution uniformly, standing for 15-20min, and dripping into cells. After 24h of cell transfection, the original culture medium is discarded, 4mL of physiological saline is washed twice, 1mL of pancreatin is added and then is put into an incubator to be digested for 1-2min, the cells are transferred into a centrifuge tube, the centrifugation is carried out for 3min at 800r, the supernatant is discarded, the DMEM culture medium with 10% fetal bovine serum is added, and the cells are repeatedly blown until the cells are uniformly mixed, and the temperature of the cells is 1.5 x 10 5 Wells were seeded in 96-well plates at 37℃with 5% CO 2 Culturing in an incubator for 24 hours. After 24h of cell plating, the stock solution of the compound 11799 was diluted with physiological saline to give final concentrations of 10, respectively -10 M、10 -9 M、10 -8 M、10 -7 M、10 -6 M、10 -5 M, compound 1179910 μl/well was added at various concentrations. After 24h of cell administration, the culture supernatant was discarded, 50. Mu.l/well of Bright-Glo reagent was added, and the chemiluminescent intensity was measured using an M5 microplate reader.
Experimental results: HEK293 cells were stimulated with different concentrations of compound 11799 at 10 -10 M～10 -5 In the M range, the agonism of the compound 11799 shows good concentration dependence, namely, the stronger the agonism is as the concentration of the compound 11799 is increased, the calculated half-effective concentration of the compound 11799 is 8.97 x 10 -8 M. The results are shown in Table 2 and FIG. 3.
Table 2 activation of the vasopressin receptor by Compounds 11799
Example 5 activation of other GPCR receptors by Compounds 11799
The experimental method comprises the following steps: HEK293 cells were cultured in a high sugar culture medium of 4.5g/L DMEM containing 10% inactivated fetal bovine serum at 37℃in 5% CO 2 In a cell incubator. When the cell density reached 80%, subculture was performed at a ratio of 1:3. When the cell fusion reached 70%, the original medium was discarded and the culture was continued with 8ml DMEM for 4 hours. After 4h, 4ml of DMEM was aspirated from the medium and 4ml of DMEM medium containing 10% foetal calf serum was supplemented. The GPCR plasmids FFA1, FFA2 and FFA3 are respectively transfected, the transfection solution is prepared according to the proportion of each dish of DMEM to the plasmid PEI=800 mu l to 10 mu g to 40 mu l, and the dosage of the transfection reagent is adjusted according to different plasmid concentrations. Mixing the transfection solution uniformly, standing for 15-20min, and dripping into cells. The rest of the procedure is as in example 4.
Experimental results: after the HEK293 cells are stimulated by the compounds 11799 with different concentrations, only the activation effect of the HEK293 cells transfected with UTS2R plasmids shows a concentration dependency, while the HEK293 cells transfected with FFA1, FFA2 and FFA3 plasmids have no obvious activation effect. The compound 11799 is suggested to be specific for the activation of the vasopressin receptor, while not activating other GPCR receptors. The results are shown in Table 3 and FIG. 4.
Table 3 specific activation of the vasopressin receptor by Compound 11799
Example 6 Effect of Compounds 11799 on glucose uptake by HepG2 liver cells
The experimental method comprises the following steps: hepG2 liver cells were cultured in a high sugar culture medium of 4.5g/L DMEM containing 10% inactivated fetal bovine serum, and placed at 37℃in 5% CO 2 In a cell incubator. When the cell density reached 90%, it was digested with trypsin and subcultured at a ratio of 1:3. Cells in logarithmic growth phase were taken at 100. Mu.l/well (1.10 5 After 24h,24h of inoculation in 96-well plates, the original medium was discarded and 100. Mu.l/well of phenol red-free 1640 medium containing 10% fetal bovine serum was added. Simultaneously, the stock solution of the compound 11799 is subjected to gradient dilution by normal saline to lead the final concentration to be 10 respectively -9 M、10 -8 M、10 -7 M、10 -6 M、10 -5 M, compound 1179910 μl/well was added at various concentrations. After further culturing for 48 hours, 10. Mu.l of the culture supernatant was aspirated from each well and added to a new 96 well, 10. Mu.l of the standard control and 10. Mu.l of purified water were additionally added; adding 1100 μl/hole of glucose test working solution, mixing, standing at 37deg.C for 4min, and reading absorbance at 340 nm; then adding glucose test working solution R225 μl/hole, mixing, standing at 37deg.C for 5min, and reading absorbance at 340 nm.
Experimental results: after 48h of compound 11799, the compound is administered at 10 compared with the control group -9 M-10 -5 The glucose absorption of HepG2 liver cells can be obviously promoted at the concentration of M. Wherein is 10 -5 The M effect is most pronounced. The results are shown in Table 4 and FIG. 5.
Table 4 effect of compound 11799 on HepG2 hepatocyte glucose uptake
Example 7 Effect of Compound 11799 on HepG2 liver cell lactate release
The experimental method comprises the following steps: cell cultures, plates, and procedures for administration are described in example 6. The lactic acid content detection method comprises the following steps: after 48h of cell culture, 10. Mu.l of culture medium supernatant was aspirated from each well, diluted 10-fold, 20. Mu.l was added to a new 96 well, and 20. Mu.l of standard control and 20. Mu.l of purified water were added; adding 50 mu l/hole of enzyme working solution and 10 mu l/hole of color development solution, uniformly mixing, and placing in a gas bath at 37 ℃ for accurate reaction for 10min; 100. Mu.l/well of stop solution was added thereto, and after thoroughly mixing, the absorbance was read at 530 nm.
Experimental results: after 48h of compound 11799, the compound is administered at 10 compared with the control group -9 M-10 -5 The concentration of M can obviously reduce the lactic acid release of HepG2 liver cells. The results are shown in Table 5 and FIG. 6.
TABLE 5 Effect of Compounds 11799 on HepG2 liver cell lactate release
Example 8 influence of Compound 11799 on HepG2 liver cell viability
The experimental method comprises the following steps: cell cultures, plates, and procedures for administration are described in example 6. The cell viability detection method comprises the following steps: after cell culture for 24h, the original medium was discarded, 100. Mu.l/well of CCK8 dilution was added to a 96-well plate, and incubated in an incubator at 37℃for about 30min, and absorbance was read at 450 nm.
Experimental results: after 24h of compound 11799, the compound is administered at 10 compared with the control group -9 M-10 -5 The concentration of M has no significant effect on the activity of HepG2 liver cells. The results are shown in Table 6 and FIG. 7.
Table 6 Effect of Compounds 11799 on HepG2 liver cell viability
Claims (9)
1. The use of a compound of formula (I) for the preparation of a medicament having a vasopressin receptor agonist activity; the structure of the compound is as follows:
2. the use of a compound of formula (I) for the manufacture of a medicament for the prevention or treatment of a pathophysiological or psychological condition characterized by a reduced expression or activity of vasopressin II or a vasopressin-like peptide; the structure of the compound is as follows:
3. the application of the compound shown in the formula (I) in preparing a medicament for treating and/or preventing metabolic syndrome; the structure of the compound is as follows:
4. use according to claim 3, characterized in that said metabolic syndrome comprises obesity, diabetes, diabetic complications, fatty liver, dyslipidemia, hypertension.
5. Use according to claim 3, characterized in that said metabolic syndrome comprises pathological states of metabolic disorders of proteins, fats, carbohydrates of the human body caused by various causes.
6. The use according to claim 4, wherein said diabetes comprises type 1 and type 2 diabetes; the obesity comprises obesity caused by congenital, acquired and pharmaceutical reasons; the diabetic complications refer to large and small vascular lesions of diabetes; the fatty liver comprises liver steatosis caused by various reasons; the dyslipidemia comprises hypertriglyceridemia, low-high density lipoproteinemia and hypercholesterolemia; the hypertension includes an increase in systolic and/or diastolic blood pressure, with or without functional or organic impairment of the heart, brain, kidney organs.
7. The use according to claim 4, wherein said diabetic complications comprise diabetic nephropathy, diabetic peripheral circulation dysfunction, diabetic peripheral neuropathy, diabetic eye disease, diabetic myopathy, diabetic co-hyperlipidemia.
8. The application of a pharmaceutical composition in preparing medicines for treating and/or preventing metabolic syndrome is characterized in that the pharmaceutical composition contains an effective dose of a compound shown as a formula (I) and a medicinal excipient;
9. the use according to claim 8, wherein said pharmaceutical composition comprises a controlled release, sustained release formulation and a form of microsomal drug delivery system.
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